Obsessive-compulsive disorder (OCD) affects 1-2% of children and adolescents, causing significant distress and impairments from the unrelenting obsessional thoughts and compulsive behaviors. Approximately 1/4 of children with OCD report an abrupt, dramatic onset of their symptoms. When these symptoms are accompanied by other behavior problems, cognitive changes and somatic symptoms, the child may qualify for a diagnosis of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). PANS is characterized by the sudden onset of OCD and/or eating disorder, accompanied by at least two of the following seven comorbidities: 1) Anxiety; 2) Emotional lability and/or depression; 3) Irritability, aggression and/or severely oppositional behaviors; 4) Behavioral (developmental) regression; 5) Deterioration in school performance; 6) Sensory or motor abnormalities; 7) Somatic signs and symptoms, including sleep disturbances, enuresis or urinary frequency and others. For a full description, see: Chang K et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacology 2015. 25(1): p 3-13. The clinical description of PANS arose from investigations of a group of children with acute-onset OCD whose symptoms appeared to arise as a consequence of common childhood infections, including Group A streptococcal (GAS) infections (strep throat and Scarlet fever). Children whose symptoms begin or exacerbate following GAS infections may belong to a subgroup of neuropsychiatric disorders identified by the acronym PANDAS (for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections). The postulated etiology for the PANDAS subgroup is that specific strains of Group A streptococci (GAS), in genetically susceptible individuals, elicit the production of cross-reactive antibodies which recognize antigens not only on the GAS cell wall, but also in the host brain tissue, eliciting obsessions, compulsions, tics and other neuropsychiatric symptoms. The cross-reactive antibodies have been shown to correlate with other anti-streptococcal antibodies and also with neuropsychiatric symptom severity, with highest titers seen in children acutely ill with Sydenham chorea or PANDAS symptomatology. Research at NIH and elsewhere has revealed that: the PANDAS subgroup has a specific and identifiable symptom course (marked most notably by the acute, abrupt, overnight onset of symptoms (zero to sixty in less than 24 hours); the cross-reactive antibodies correlate with both GAS infection status and neuropsychiatric symptom severity; passive transfer of the cross-reactive antibodies replicated disease symptoms in animal models; prevention of GAS infections through antibiotic prophylaxis results in prevention of neuropsychiatric symptom exacerbations; and, treatment of acutely ill children with immunomodulatory therapies specifically, intravenous immunoglobulin (IVIG) or plasmapheresis, may produce dramatic reductions in symptom severity. This line of research is unusual, in that it reverses the typical bench to bedside progression and takes clinical observations into the laboratory in search of information about etiopathogenic mechanisms. This approach is yielding exciting results, as serum samples from acutely ill children contain cross-reactive antibodies which target brain antigens, presumably triggering the clinical manifestations. Identification of the antigenic targets may provide new targets for therapeutic interventions. Dr. Swedo, Dr. James Leckman and colleagues at the Yale University Child Study Center, and Dr. Madeleine Cunningham of the University of Oklahoma Health Sciences Center were the joint recipients of an NIH Bench to Bedside award which helped fund a multi-site placebo-controlled trial of intravenous immunoglobulin (IVIG) for severely ill children with PANDAS (Protocol 11-M-0058, NCT 01281969). More than 40 children (3-12 years old) enrolled in the trial and 35 were randomly assigned to receive an infusion of IVIG or placebo. Although there were no significant differences between the IVIG and placebo groups, open-label treatment with IVIG produced improvements in over 80% of the children. (Williams et al, JAACAP 2016) Data and samples from the study are being used in attempts to identify predictors of treatment response, as well as biomarkers of disease severity. Dr. Swedo is currently leading efforts to create a nationwide collaborative PANS/PANDAS clinical research network with the goals of (1) improving recognition, diagnosis, and treatment of acute onset neuropsychiatric syndromes, (2) conducting research which improves understanding of etiologic factors, host vulnerability, and disease mechanisms, and c) increasing awareness and recognition of PANDAS, PANS, and related disorders in order to improve access to care. The inaugural meeting of the Network was held early in 2016, with 14 academic institutions represented. In addition to agreeing on common measures for diagnostic assessment, the attendees agreed to develop guidelines for treatment of PANS/PANDAS. The guidelines are being published by the Journal of Child & Adolescent Psychopharmacology as a set of four papers which provide a comprehensive approach to clinical management (Swedo et al) and include recommendations for use of psychiatric medications and cognitive-behavior therapy (Thienemann et al), as well as treatment with antibiotics (Cooperstock et al) and immunomodulatry therapies (Frankovich et al)(J Child Adol Psychopharmacology Sep 2017, Vol 7, Issue 7, pages 562-606)